Incorporating receptor theory in mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) modeling

Abstract

Pharmacokinetic-Pharmacodynamic (PK-PD) modeling helps to better understand drug efficacy and safety and has, therefore, become a powerful tool in the learning-confirming cycles of drug-development. In translational drug research, mechanism-based PK-PD modeling has been recognized as a tool for bringing forward early insights in drug efficacy and safety into the clinical development. These models differ from descriptive PK-PD models in that they quantitatively characterize specific processes in the causal chain between drug administration and effect. This includes target site distribution, binding and activation, pharmacodynamic interactions, transduction and homeostatic feedback mechanisms. Compared to descriptive models mechanism-based PK-PD models that utilize receptor theory concepts for characterization of target binding and target activation processes have improved properties for extrapolation and prediction. In this respect, receptor theory constitutes the basis for 1) prediction of in vivo drug concentration-effect relationships and 2) characterization of target association-dissociation kinetics as determinants of hysteresis in the time course of the drug effect. This approach intrinsically distinguishes drug- and system specific parameters explicitly, allowing accurate extrapolation from in vitro to in vivo and across species. This review provides an overview of recent developments in incorporating receptor theory in PK-PD modeling with a specific focus on the identifiability of these models.